Imbalances of gamma globulin subgroups and gene defects in patients with primary hypogammaglobulinemia.

Analysis of immunoglobulin classes, gammaG subgroups, and Gm genetic markers from 59 patients with various types of immune deficiencies was undertaken to assess the function of the several cistrons concerned with synthesis of gamma globulins. 13 patients including two sibling pairs were found to have gammaG subgroup imbalances. All of these patients had non sex-linked disease. 11 of the 13 had preponderance of the gammaG3 subgroup. In most instances of gammaG3 preponderance it was the Gm(b) type of gammaG3 that was selectively retained; the Gm(g) type, controlled by the allelic gene was markedly depressed but not absent in the cases where it could be studied. Other imbalances, either seen concomitantly with gammaG3 preponderance or independently, included predominance of the gammaG2 subgroup and selective absence of single gammaG subgroups.One family was encountered with probable structural gene abnormalities in the autosomal Gm loci. Both parents had different abnormal gene complexes detectable by absence of specific Gm markers and the propositus received both types from the parents. Similar gene complexes have been seen previously in rare instances through population screening but only in the heterozygous state and were not associated with clinically evident hypogammaglobulinemia. Of several other families of patients with subgroup imbalance, two were informative in that structural gene defects could be excluded. Studies on 22 first degree relatives of patients with subgroup imbalances indicated that the most common abnormality detected was in gammaA which was absent in 3 and markedly decreased in 2 others; other abnormalities included decreased levels of specific genetic types of gammaG globulin. It is concluded that gammaG subgroup imbalances are frequently found in non sex-linked immunoglobulin deficiency disorders and in some instances may be associated with family abnormalities suggesting either regulator or structural gene defects.